Abstract Epilepsy is one of the most common neurological disorders, with a lifetime cumulative incidence of nearly 4%. Amongst the epilepsies, Lafora Disease (LD) is the one most ready for personalized treatment. The molecular basis of LD is known with 65-70% of LD cases due to mutations in the EPM2A gene encoding the glycogen phosphatase, laforin, and 25-30% of LD cases due to mutations in EPM2B, the gene encoding the E3 ubiquitin ligase, malin. The hallmark of LD is the accumulation of starch-like polyglucosans called Lafora bodies (LBs), which present clinically as an intractable fatal epilepsy. To support the work proposed in this grant, the Biological Core will generate transgenic cell culture and mouse models to both study LD mechanisms and evaluate putative therapeutics. The core will use CRISPR technilogy to genetically manipulate SY5Y (human nueronal cell line) and induced pluripotent stem cells (iPSc) to harbor a LD missense mutation and a premature stop codon in both the lafonin and malin genes (8 cell lines total). These cells will be evaluated for their ability to differentiate into neurons and produce LBs . These cell lines will be used in high throughput drug screens and testing of lead compounds. The core will also generate 4 mouse models by introducing the same LD mutations for laforin and malin used in the cell culture models. Video-EEG and behavioral studies will document drug effects on epilepsy and behavior of LD transgenic mice. These mouse models will be used by in Projects 1-4 to determine the efficacy of promising drugs obtained from the high throughput screens and define the window of opportunity for treatment. The ultimate goal of the PIs associated with this program project grant is to combine our efforts to cure Lafora Disease.